4-Thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamides as antiviral agents

ABSTRACT

The invention provides a compound of formula I:  
                 
 
     wherein R 1 , R 2 , R 3 , and R 4  have any of the values defined in the specification, or a pharmaceutically acceptable salt thereof, as well as processes and intermediates useful for preparing such compounds or salts, and methods of treating a herpesvirus infection, atherosclerosis or restenosis using such compounds or salts.

RELATED APPLICATIONS

[0001] This applications claims priority to U.S. Provisional PatentApplication No. 60/316,129, filed Aug. 30, 2001, which is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The present invention provides4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide derivatives,more specifically,5-benzylaminothiocarbonyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridinederivatives of formula (I), which are useful as antiviral agents (e.g.as agents against viruses of the herpes family).

BACKGROUND OF THE INVENTION

[0003] The herpesviruses comprise a large family of double stranded DNAviruses. They are also a source of the most common viral illnesses inman. Eight of the herpes viruses, herpes simplex virus types 1 and 2(HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus(HCMV), epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8(HHV-6, HHV-7, and HHV-8), have been shown to infect humans.

[0004] HSV-1 and HSV-2 cause herpetic lesions on the lips and genitals,respectively. They also occasionally cause infections of the eye andencephalitis. HCMV causes birth defects in infants and a variety ofdiseases in immunocompromised patients such as retinitis, pneumonia, andgastrointestinal disease. VZV is the causative agent of chicken pox andshingles. EBV causes infectious mononucleosis. It can also causelymphomas in immunocompromised patients and has been associated withBurkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkins disease.HHV-6 is the causative agent of roseola and may be associated withmultiple sclerosis and chronic fatigue syndrome. HHV-7 diseaseassociation is unclear, but it may be involved in some cases of roseola.HHV-8 has been associated with Karposi's sarcoma, body cavity basedlymphomas, and multiple myeloma.

[0005] Infection by or reactivation of herpesviruses is also associatedwith several cardiovascular diseases or conditions in the host such asatherosclerosis and restenosis resulting in inflammation of coronaryvessel walls. It is thought that in many patients suffering fromrestenosis following coronary atherectomy, viral infection, particularlyby CMV, plays an important role in the proliferation of the disease.Atherosclerosis is believed to be associated with the overall infectiousdisease burden in the host and particularly by the herpesviruses such asHSV, CMV, and EBV. Infection in the animal population (livestock andcompanion) by strains of herpesviruses is endemic including cattle(Bovine herspesvirus 1-5, BHV), sheep (Ovine herpesvirus 1 and 2), dog(Canine herpesvirus 1), horse (Equine herpesvirus 1-8, EHV), cat (Felineherpesvirus 1, FHV), swine (pseudorabies virus, PRV), and many speciesof fowl. In the case of bovine herpesvirus infection, animals may sufferfrom ocular, respiratory, or digestive disorders. Pseudorabies is anextremely contagious viral pathogen infecting several species such ascattle, horses, dogs, cats, sheep, and goats leading to rapid death. Thevirus is benign in adult swine, however, it remains contagious and leadsto high mortality in pigs under three weeks. Infection of horses byequine herpesvirus may lead to neurological syndromes, respiratorydisease, and neonatal disease. Herpesvirus infection in cats leads tothe disease known as feline viral rhinotracheitis (FVR) which ischaracterized by rhinitis, tracheitis, laryngitis, and conjunctivitis.

SUMMARY OF THE INVENTION

[0006] The present invention provides a compound of formula I:

[0007] or a pharmaceutically acceptable salt thereof wherein,

[0008] R¹ is

[0009] (a) Cl,

[0010] (b) Br,

[0011] (c) CN,

[0012] (d) NO₂, or

[0013] (e) F;

[0014] R² is

[0015] (a) H,

[0016] (b) R⁵,

[0017] (c) NR⁷R⁸,

[0018] (d) SO₂R⁹, or

[0019] (e) OR⁹;

[0020] R³ is

[0021] (a) H,

[0022] (b) halo,

[0023] (c) aryl,

[0024] (d) S(O)_(m)R⁶,

[0025] (e) (C═O)R⁶,

[0026] (f) (C═O)OR⁹,

[0027] (g) cyano,

[0028] (h) het, wherein said het is bound via a carbon atom,

[0029] (i) OR¹⁰,

[0030] (j) Ohet,

[0031] (k) NR⁷R⁸

[0032] (l) SR¹⁰,

[0033] (m) Shet,

[0034] (n) NHCOR¹²,

[0035] (o) NHSO₂R¹², or

[0036] (p) C₁₋₇alkyl which may be partially unsaturated and optionallysubstituted by one or more substituents of the group R¹¹, OR¹³, SR¹⁰,SR¹³, NR⁷R⁸, halo, (C═O)C₁₋₇alkyl, or SO_(m)R⁹;

[0037] R⁴ is

[0038] (a) H,

[0039] (b) halo,

[0040] (c) C₁₋₄alkyl, or

[0041] (d) R⁴ together with R³ form a carbocyclic or het, either ofwhich may be optionally substituted by NR⁷R⁸, by C₁₋₇alkyl which may beoptionally substituted by OR⁴, or by het, wherein said het is bound viaa carbon atom;

[0042] R⁵ is

[0043] (a) (CH₂CH₂O)₁R¹⁰,

[0044] (b) het, wherein said het is bound via a carbon atom,

[0045] (c) aryl,

[0046] (d) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected from a groupconsisting of NR⁷R⁸, R¹¹, SO_(m)R⁹, and OC₂₋₄alkyl which may be furthersubstituted by het, OR¹⁰, or NR⁷R⁸, or

[0047] (e) C₃₋₈cycloalkyl which may be partially unsaturated andoptionally substituted by one or more substituents selected from a groupconsisting of R¹¹, NR⁷R⁸, SO_(m)R⁹, and C₁₋₇alkyl optionally substitutedby R¹¹, NR⁷R⁸, or SO_(m)R⁹;

[0048] R⁶ is

[0049] (a) C₁₋₇alkyl,

[0050] (b) NR⁷R⁸,

[0051] (c) aryl, or

[0052] (d) het, wherein said het is bound via a carbon atom;

[0053] R⁷ and R⁸ are independently

[0054] (a) H,

[0055] (b) aryl,

[0056] (c) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected from a groupconsisting of NR¹⁰R¹⁰, R¹¹, SO_(m)R⁹, CONR¹⁰R¹⁰, or halo, or,

[0057] (d) R⁷ and R⁸ together with the nitrogen to which they areattached form a het;

[0058] R⁹ is

[0059] (a) aryl,

[0060] (b) het,

[0061] (c) C₃₋₈cycloalkyl, or

[0062] (d) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected from a groupconsisting of NR¹⁰R¹⁰, R¹¹, SH, CONR¹⁰R¹⁰, or halo;

[0063] R¹⁰ is

[0064] (a) H, or

[0065] (b) C₁₋₇alkyl optionally substituted by OH;

[0066] R¹¹ is

[0067] (a) OR¹⁰,

[0068] (b) Ohet,

[0069] (c) Oaryl,

[0070] (d) CO₂R¹⁰,

[0071] (e) het,

[0072] (f) aryl, or

[0073] (g) CN;

[0074] R¹² is

[0075] (a) H,

[0076] (b) het,

[0077] (c) aryl,

[0078] (d) C₃₋₈cycloalkyl, or

[0079] (e) C₇alkyl optionally substituted by NR⁷R⁸ or R¹¹;

[0080] R¹³ is

[0081] (a) (P═O)(OR¹⁴)₂,

[0082] (b) CO(CH₂)_(n)CON(CH₃)—(CH₂)_(n)SO₃ ⁻M⁺,

[0083] (c) an amino acid,

[0084] (d) C(═O)aryl, or

[0085] (e) C(═O)C₁₋₇alkyl optionally substituted by NR⁷R⁸, aryl, het,CO₂H, or O(CH₂)_(n)CO₂R¹⁴);

[0086] R¹⁴ is

[0087] (a) H, or

[0088] (b) C₁₋₇alkyl;

[0089] each i is independently 2, 3, or 4;

[0090] each n is independently 1, 2, 3, 4 or 5;

[0091] each m is independently 0, 1, or 2;

[0092] M is sodium, potassium, or lithium;

[0093] wherein any aryl is optionally substituted with one or moresubstituents selected from the group consisting of halo, OH, cyano,CO₂R¹⁴, CF₃, C₁₋₆alkoxy, and C₁₋₆ alkyl which maybe further substitutedby one to three SR¹⁴, NR¹⁴R¹⁴, OR¹⁴, het, or CO₂R¹⁴; and

[0094] wherein any het is optionally substituted with one or moresubstituents selected from the group consisting of halo, OH, cyano,phenyl, CO₂R¹⁴, CF₃, C₁₋₆alkoxy, oxo, oxime, and C₁₋₆ alkyl which maybefurther substituted by one to three SR¹⁴, NR¹⁴R¹⁴, OR⁴, or CO₂R⁴.

[0095] In another aspect, the present invention also provides:

[0096] a pharmaceutical composition comprising a compound of formula I,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient (the composition preferably comprises an effectiveantiviral amount of the compound or salt);

[0097] a method of treating a herpesviral infection, comprisingadministering to a mammal (e.g. a human) in need of such treatment, acompound of formula (I) or a pharmaceutically acceptable salt thereof;

[0098] a method for treating atherosclerosis or restenosis in a mammalcomprising, administering to a mammal in need of such treatment, aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof;

[0099] a compound of formula (I) or a pharmaceutically acceptable saltthereof for use in medical treatment (e.g. the treatment of aherpesviral infection);

[0100] the use of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof to prepare a medicament for treating aherpesviral infection in a mammal (e.g. a human); and

[0101] a method for inhibiting a viral DNA polymerase, comprisingcontacting (in vitro or in vivo) the polymerase with an effectiveinhibitory amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof.

[0102] The invention also provides novel intermediates and processesdisclosed herein that are useful for preparing compounds of formula I.

[0103] Compounds of formula I have a 4-substitutedbenzylthioaminocarbonyl substituent at the 5-position of thethieno[2,3-b]pyridine ring system. This substitution pattern has beenfound to provide compounds with significantly improved antiviralactivity compared to thienopyridines lacking this substitution.

DETAILED DESCRIPTION OF THE INVENTION

[0104] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote bothstraight and branched groups; but reference to an individual radicalsuch as “propyl” embraces only the straight chain radical, a branchedchain isomer such as “isopropyl” being specifically referred to. Whenalkyl can be partially unsaturated, the alkyl chain may comprise one ormore (e.g. 1, 2, 3, or 4) double or triple bonds in the chain.

[0105] Aryl denotes a phenyl radical or an ortho-fused bicycliccarbocyclic radical having about nine to ten ring atoms in which atleast one ring is aromatic. Het is a four- (4), five- (5), six- (6), orseven- (7) membered saturated or unsaturated heterocyclic ring having 1,2, 3, or 4 heteroatoms selected from the group consisting of oxy, thio,sulfinyl, sulfonyl, and nitrogen, which is optionally fused to a benzenering, or any bicyclic heterocycle group. Het includes “heteroaryl,”which encompasses a radical attached via a ring carbon of a monocyclicaromatic ring containing five or six ring atoms consisting of carbon and1, 2, 3, or 4 heteroatoms each selected from the group consisting ofnon-peroxide oxy, thio, and N(X) wherein X is absent or is H, O,C₁₋₄alkyl, phenyl or benzyl, as well as a radical of an ortho-fusedbicyclic heterocycle of about eight to ten ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, or tetramethylene diradical thereto.

[0106] When R⁴ together with R³ form a carbocyclic, R⁴ and R³ togethercan be a 2, 3, 4, 5, or 6 membered saturated or unsaturated carbonchain, which chain can optionally be fused to a benzene ring.

[0107] “Amino acid,” includes a residue of natural amino acid (e.g. Ala,Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met,Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as well asunnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Anamino acid can conveniently be linked to the remainder of a compound offormula I through the carboxy terminus, the amino terminus, or throughany other convenient point of attachment, such as, for example, throughthe sulfur of cysteine. In particular, an amino acid can conveniently belinked to the remainder of a compound of formula I through the carboxyterminus.

[0108] “Treating” includes (i) preventing a pathologic condition fromoccurring (e.g. prophylaxis); (ii) inhibiting the pathologic conditionor arresting its development; and (iii) relieving the pathologiccondition.

[0109] It will be appreciated by those skilled in the art that compoundsof the invention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, tautomeric, orstereoisomeric form, or mixture thereof, of a compound of the invention,which possesses the useful properties described herein, it being wellknown in the art how to prepare optically active forms (for example, byresolution of the racemic form by recrystallization techniques, bysynthesis from optically-active starting materials, by chiral synthesis,or by chromatographic separation using a chiral stationary phase) andhow to determine antiviral activity using the standard tests describedherein, or using other similar tests which are well known in the art. Inparticular, it is understood that compounds of formula I wherein R² ishydrogen can exist in the corresponding tautomeric “enol” form, and thatsuch tautomers are included as compounds of the invention.

[0110] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating a lower and upper numberof carbon atoms in the moiety, i.e., the prefix C_(i-j) indicates amoiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, C₁₋₇alkyl refers to alkyl of one to seven carbonatoms, inclusive.

[0111] The compounds of the present invention are generally namedaccording to the IUPAC or CAS nomenclature system. Abbreviations whichare well known to one of ordinary skill in the art may be used (e.g.“Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hoursand “rt” for room temperature).

[0112] Specific and preferred values listed below for radicals,substituents, and ranges, are for illustration only; they do not excludeother defined values or other values within defined ranges for theradicals and substituents. The compounds of the invention includecompounds of formula I having any combination of the values, specificvalues, more specific values, and preferred values described herein.

[0113] Specifically, C₁₋₇alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or heptyl;C₃₋₈cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, or cyclooctyl; C₁₋₇alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy,hexyloxy, 1-methylhexyloxy, or heptyloxy; C(═O)C₁₋₇alkyl can be acetyl,propanoyl, butanoyl, pentanoyl, 4-methylpentanoyl, hexanoyl, orheptanoyl; aryl can be phenyl, indenyl, or naphthyl; het can bepyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or heteroaryl;and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl,isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl,tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or itsN-oxide).

[0114] When C₁₋₇alkyl is partially unsaturated, it can specifically bevinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexene-1-ynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, or 5-hexynyl.

[0115] A specific value for Het is a five- (5), six- (6), or seven- (7)membered saturated or unsaturated ring containing 1, 2, 3, or 4heteroatoms selected from the group consisting of non-peroxide oxy,thio, sulfinyl, sulfonyl, and nitrogen; as well as a radical of anortho-fused bicyclic heterocycle of about eight to twelve ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, tetramethylene or another monocyclichet diradical thereto.

[0116] A specific value for R¹ is F, Cl, or Br.

[0117] A more specific value for R¹ is Cl.

[0118] A specific value for R² is H.

[0119] 5. A specific value for R² is R⁵, NR⁷R⁸, SO₂R⁹, or OR⁹.

[0120] A specific value for R² is R⁵.

[0121] A more specific value for R² is methyl, ethyl, propyl, isopropyl,butyl, tert-butyl, carboxymethyl, (C₁₋₇ alkoxy)carbonylmethyl,2-hydroxyethyl, 2-(2-methoxyethoxy)ethyl,3-(2-tetrahydropyranyloxy)propyl, 2-morpholinoethyl,2-(diethylamino)ethyl, 2-(dimethylamino)ethyl, 2-piperidinoethyl,3-piperidinopropyl, 2-(1-methylpyrrolidin-2-yl)ethyl,2-(diisopropylamino)ethyl, 2-pyrrolidin-1-ylethyl,3-(dimethylamino)propyl, benzyl, 3-fluorobenzyl, 3-phenylpropyl,2-tetrahydrofuranylmethyl, 2-pyrrolidinoethyl, 3-pyridylmethyl, orvinyl.

[0122] A more specific value for R² is methyl, ethyl, isopropyl,2-hydroxyethyl, 2-(diethylamino)ethyl, or 2-(dimethylamino)ethyl.

[0123] A specific value for R³ is H, halo, S(O)_(n)R⁶, (C═O)R⁶,(C═O)OR⁹, cyano, or C₁₋₇alkyl which may be partially unsaturated andoptionally substituted by one or more substituents of the group R¹¹,OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo, (C═O)C₁₋₇alkyl, and SO_(m)R⁹.

[0124] A specific value for R³ is C₁₋₇alkyl which may be partiallyunsaturated and optionally substituted by one or more substituents ofthe group R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo, (C═O)C₁₋₇alkyl, andSO_(m)R⁹.

[0125] A specific value for R³ is C₁₋₇alkyl which may be partiallyunsaturated and is substituted by one or more substituents of the groupR¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo, (C═O)C₁₋₇alkyl, and SO_(m)R⁹.

[0126] A specific value for R³ is C₁₋₇alkyl which may be partiallyunsaturated and is substituted by one or more substituents of the groupOR¹⁰, het and NR⁷R⁸.

[0127] A specific value for R³ is (Z or E)-CH═CH(CH₂)_(n)R_(a) or—C≡C(CH₂)_(n)R_(a) wherein R_(a) is R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo,(C═O)C₁₋₇alkyl, or SO_(m)R⁹.

[0128] A more specific value for R³ is bromo, iodo,3-hydroxy-1-propynyl, 3-methoxy-1-propynyl, 4-hydroxy-1-butynyl,3-hydroxypropyl, cyano, 4,4-di(methoxycarbonyl)-1-butynyl,4-hydroxybutyl, 3-(3-carboxypropanoyloxy)-1-propynyl,3-(morpholinoacetoxy)-1-propynyl,3-(2-amino-3-methylbutanoyloxy)-1-propynyl, or thiomorpholinomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-methyl)aminomethyl,morpholinocarbonyl, 3-[3-(morpholinomethyl)benzoyloxy]-1-propynyl.

[0129] A more specific value for R³ is iodo, 3-hydroxy-1-propynyl,4-hydroxy-1-butynyl, 3-hydroxypropyl, morpholinomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl or4-hydroxybutyl.

[0130] A specific value for R³ is 3-hydroxy-1-propynyl,morpholinomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl or3-hydroxypropyl.

[0131] A specific value for R⁵ is (CH₂CH₂O)_(i)R¹⁰.

[0132] A specific value for R⁵ is C₁₋₇alkyl which may be partiallyunsaturated and is optionally substituted by one or more substituentsselected from a group consisting of NR⁷R⁸, R, SO_(m)R⁹, and OC₂₋₄alkyl,which may be further substituted by het, OR¹⁰, or NR⁷R⁸; wherein R⁹ andR¹⁰ have any of the values defined herein; and

[0133] wherein

[0134] R⁷ and R⁸ are independently

[0135] (a) H,

[0136] (b) aryl, or

[0137] (c) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected from a groupconsisting of NR¹⁰R¹⁰, R¹¹, SO_(m)R⁹, CONR¹⁰R¹⁰, or halo; and,

[0138] R¹¹ is

[0139] (a) OR¹⁰,

[0140] (b) Ohet,

[0141] (c) Oaryl,

[0142] (d) CO₂R¹⁰, or

[0143] (g) CN.

[0144] A specific value for R⁵ is C₁₋₇alkyl which may be partiallyunsaturated and is optionally substituted by one or more substituentsselected from a group consisting of NR⁷R⁸, R¹¹, SO_(m)R⁹, andOC₂₋₄alkyl, which may be further substituted by het, OR¹⁰, or NR⁷R⁸.

[0145] A specific value for R⁵ is C₁₋₇alkyl, which may be partiallyunsaturated and is optionally substituted by one or more aryl or het.

[0146] A more specific value for R⁵ is C₁₋₇alkyl.

[0147] A specific compound of formula I is a compound wherein any aryl,or het is optionally substituted with one or two substituents selectedfrom the group consisting of halo, cyano, het trifluoromethyl,trifluoromethoxy, hydroxy C₁₋₇alkoxy, and C₁₋₇alkyl; or apharmaceutically acceptable salt thereof.

[0148] Preferred compounds of formula I exclude compounds disclosedspecifically or generically in the references cited herein.

[0149] The preparation of starting materials and intermediate4-oxo-compounds useful for preparing the thioxo-carbothioamide compoundsof the present invention are disclosed in U.S. Pat. No. 6,239,142 andInternational Patent Applicaiton Publication No. WO-00/53610. Charts Aand B describe the preparation of thioxo-carbothioamide compounds of thepresent invention.

[0150] In Chart A, ketone-amide A-1 is reacted with Lawesson's reagentin the presence of KHMDS in refluxing toluene to furnish the thioketonecarbothioamide A-2:

[0151] The hydroxypropyl compound B-1 is reacted in DMF with TIPSCl inthe presence of imidiazole to afford B-2. The ketone B-2 is reacted withLawesson's reagent in the presence of KHMDS in refluxing toluene tofurnish the protected alcohol thioketone-carboxthioamide B-3. Theprotected alcohol B-3 is then treated with Bu₄N⁺F in THF affording thehydroxyl compound B-4.

[0152] The invention also provides processes and intermediates describedherein that are useful for preparing compounds of the invention. Forexample, the invention provides a method for preparing athioxo-carbothioamide compound of formula I:

[0153] wherein R¹-R⁴ have the above values, comprising reacting acorresponding compound of formula II:

[0154] with Lawesson's Reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) toprovide a compound of formula I. The above transformation can besimilarly accomplished with other alternative or equivalent suitablethionating reagents, for example, P₂S₅, see Lightner, D. A. et al., J.Am. Chem. Soc., 1984, 106, 934, and Spear, G. W. et al., Synth. Commun.,2000, 30, 565; P₄S₁₀, see Hartke, K. et al., J. Prakt, Chem./Chem-Ztg,1996, 338, 251; Belleau reagent, see Belleau, B. et al., TetrahedronLett., 1983, 24, 3815; and polymer thionating reagent, see Ley, S. V. etal., J. Chem. Soc. Perkin Trans. 1., 2001, 358. In cases where compoundsare sufficiently basic or acidic to form stable nontoxic acid or basesalts, administration of the compounds as salts may be appropriate.Examples of pharmaceutically acceptable salts are organic acid additionsalts formed with acids which form a physiological acceptable anion, forexample, tosylate, methanesulfonate, acetate, citrate, malonate,tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, andα-glycerophosphate. Suitable inorganic salts may also be formed,including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate,and carbonate salts.

[0155] Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal (for example, sodium,potassium or lithium) or alkaline earth metal (for example calcium)salts of carboxylic acids can also be made.

[0156] Compounds of the present invention can conveniently beadministered in a pharmaceutical composition containing the compound incombination with a suitable excipient, the composition being useful incombating viral infections. Pharmaceutical compositions containing acompound appropriate for antiviral use are prepared by methods andcontain excipients which are well known in the art. A generallyrecognized compendium of such methods and ingredients is Remington'sPharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed.,1975). The compounds and compositions of the present invention can beadministered parenterally (for example, by intravenous, intraperitonealor intramuscular injection), topically, orally, or rectally, dependingon whether the preparation is used to treat internal or external viralinfections.

[0157] For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparations shouldcontain at least 0.1% of active compound. The percentage of thecompositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of active compound in such therapeuticallyuseful compositions is such that an effective dosage level will beobtained.

[0158] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fructose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0159] The compounds or compositions can also be administeredintravenously or intraperitoneally by infusion or injection. Solutionsof the active compound or its salts can be prepared in water, optionallymixed with a nontoxic surfactant. Dispersions can also be prepared inglycerol, liquid polyethylene glycols, triacetin, and mixtures thereofand in oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

[0160] Pharmaceutical dosage forms suitable for injection or infusioncan include sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

[0161] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

[0162] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

[0163] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include water, alcohols or glycols orwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid ofnon-toxic surfactants. Adjuvants such as fragrances and additionalantimicrobial agents can be added to optimize the properties for a givenuse. The resultant liquid compositions can be applied from absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers. Thickeners suchas synthetic polymers, fatty acids, fatty acid salts and esters, fattyalcohols, modified celluloses or modified mineral materials can also beemployed with liquid carriers to form spreadable pastes, gels,ointments, soaps, and the like, for application directly to the skin ofthe user.

[0164] Examples of useful dermatological compositions which can be usedto deliver the compounds of formula I to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

[0165] Useful dosages of the compounds of formula I can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

[0166] The compound is conveniently administered in unit dosage form;for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

[0167] For internal infections, the compositions can be administeredorally or parenterally at dose levels, calculated as the free base, ofabout 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal bodyweight, and can be used in man in a unit dosage form, administered oneto four times daily in the amount of 1 to 1000 mg per unit dose.

[0168] For parenteral administration or for administration as drops, asfor eye infections, the compounds are presented in aqueous solution in aconcentration of from about 0.1 to about 10%, more preferably about 0.1to about 7%. The solution may contain other ingredients, such asemulsifiers, antioxidants or buffers.

[0169] Generally, the concentration of the compound(s) of formula I in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt %. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt %,preferably about 0.5-2.5 wt %.

[0170] The exact regimen for administration of the compounds andcompositions disclosed herein will necessarily be dependent upon theneeds of the individual subject being treated, the type of treatmentand, of course, the judgment of the attending practitioner.

[0171] The antiviral activity of a compound of the invention can bedetermined using pharmacological models which are well known to the art,or using Test A described below.

[0172] The compounds of formula (I) and pharmaceutically acceptablesalts thereof are useful as antiviral agents. Thus, they are useful tocombat viral infections in animals, including man. The compounds aregenerally active against herpes viruses, and are particularly usefulagainst the varicella zoster virus, the Epstein-Barr virus, the herpessimplex virus, the human herpes virus type 8 (HHV-8) and thecytomegalovirus (CMV).

[0173] While many of the compounds of the present invention have shownactivity against the CMV polymerase, these compounds may be activeagainst the cytomegalovirus by this or other mechanisms of action. Thus,the description below of these compounds' activity against the CMVpolymerase is not meant to limit the present invention to a specificmechanism of action.

[0174] Test A.

[0175] The HCMV polymerase assay is performed using a scintillationproximity assay (SPA) as described in several references, such as N. D.Cook, et al., Pharmaceutical Manufacturing International, pages 49-53(1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S.Pat. No. 4,568,649 (1986); which are incorporated by reference herein.Reactions are performed in 96-well plates. The assay is conducted in 100μl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl₂, 0.36mg/ml BSA, and 90 nM H-dTTP. Assays are run with and without CHAPS,(3-[(3-cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a finalconcentration of 2 mM. HCMV polymerase is diluted in enzyme dilutionbuffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100μg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which isexpressed in recombinant baculovirus-infected SF-9 cells and purifiedaccording to literature procedures, is added at 10% (or 10 μl) of thefinal reaction volume, i.e., 100 μl. Compounds are diluted in 50% DMSOand 10 μl are added to each well. Control wells contain an equivalentconcentration of DMSO. Unless noted otherwise, reactions are initiatedvia the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primerto reaction mixtures containing the enzyme, substrate, and compounds ofinterest. Plates are incubated in a 25 C or 37 C H₂O bath and terminatedvia the addition of 40 μl/reaction of 0.5 M EDTA (pH 8) per well.Reactions are terminated within the time-frame during which substrateincorporation is linear and varied depending upon the enzyme andconditions used, i.e., 30 min. for HCMV polymerase. Ten μl ofstreptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are addedfollowing termination of the reaction. Plates are incubated 10 min. at37° C., then equilibrated to room temperature, and counted on a PackardTopcount. Linear regressions are performed and IC₅₀'s are calculatedusing computer software.

[0176] A modified version of the above HCMV polymerase assay isperformed as described above, but with the following changes: Compoundsare diluted in 100% DMSO until final dilution into assay buffer. In theprevious assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol(DTT) is added to the polymerase buffer. Also, a different lot of CMVpolymerase is used, which appears to be more active resulting in a morerapid polymerase reaction. Results of the testing for a representativecompound of formula I in this assay are shown in Table 1. In Table 1,the term “nd” refers to activity data not determined. TABLE 1 BiologicalData polymerase IC₅₀ (μM) Example HCMV HSV VZV 1 0.91 0.36 0.13

DESCRIPTION OF PREFERRED EMBODIMENTS

[0177] The preparation of intermediate 4-oxo-compounds of formula IIthat can be converted to the corresponding 4-thioxo carbothioamidecompounds of formula I of the present invention are disclosed in theabove mentioned U.S. Pat. No. 6,239,142 and International PatentApplication Publication No. WO-00/53610. The following examples providerepresentative preparations of the compounds of the present invention.

EXAMPLE 1

[0178] Preparation ofN-(4-Chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide,(A-2 of Chart A) A-1 (570 mg, 1.32 mmol) was dissolved in dichloroethane(80 mL) followed by the addition of KHMDS (0.5 M, 2.64 mL, 1.32 mmol, 1equiv.). Then Lawesson's reagent (1.1 g, 2.64 mmol, 2.0 equiv.) andtoluene (80 mL) was added and the resulting mixture was heated at refluxfor 6 h. The reaction was cooled to rt, diluted with dichloromethane,washed with water, Na₂CO₃, brine, dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (heptane/EtOAc 1/1, ¼, 0/1 then DCM/MeOH 19/1) to afford248 mg of crudeN-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboamideand 139 mg of crudeN-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamideA-2. The crude A-2 was purified by multiple silica gel chromatography(heptane/EtOAc 1/1, ¼, 0/1 then DCM/MeOH 1/0, 50/1, 19/1) to afford 55mg (9%) of pure tan solid.

[0179]¹H NMR (TFA_(d1)) δ 8.59, 8.12, 7.41, 5.08, 5.02, 4.43-4.36,4.13-4.10, 3.91-3.88, 3.65-3.62. ¹³C NMR (125 MHz, CDCl₃/DMSO) δ 192.51,177.84, 144.22, 144.06, 141.96, 135.98, 132.35, 131.54, 130.02, 129.76,128.74, 128.58, 124.64, 66.57, 57.27, 53.42, 49.27, 44.52. IR (diffusereflectance) 2810, 2740, 2425, 2297, 1584, 1565, 1507, 1447, 1399, 1345,1115, 1087, 867, 860, 796, cm⁻¹.

[0180] MS (EI) m/z 463, 340, 339, 338, 252, 251, 239, 219, 125, 86, 84.

[0181] HRMS (EI) calcd for C₂₁H₂₂CLN₃OS₃+H₁ 464.0692, found 464.0680.

[0182] Anal. Calcd for C₂₁H₂₂CLN₃OS₃: C, 54.35; H, 4.78; N, 9.06; Cl,7.64; S, 20.73.

[0183] Found: C, 54.37; H, 4.86; N, 8.97.

EXAMPLE 2

[0184]N-(4-Chlorobenzyl)-7-methyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide(Chart B, B-4). The hydroxypropyl compound B-1 is reacted in DMF withTIPSCl in the presence of imidiazole to afford B-2. The ketone B-2 isreacted with Lawesson's reagent in the presence of KHMDS in refluxingtoluene to furnish the protected alcohol thioketone-carboxamide B-3. Theprotected alcohol B-3 is then treated with Bu₄N⁺F in THF affording thehydroxyl compound B-4.

EXAMPLE 3

[0185] Using procedures similar to those described herein, the followingcompounds of the invention can also be prepared.

[0186] (1)N-(4-Chlorobenzyl)-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide;

[0187] (2)N-(4-Chlorobenzyl)-4-mercapto-2-iodothieno[2,3-b]pyridine-5-carbothioamide;

[0188] (3)N-(4-Chlorobenzyl)-4-mercapto-2-(4-morpholinylsulfonyl)thieno[2,3-b]-pyridine-5-carbothioamide;

[0189] (4)2-Bromo-N-(4-chlorobenzyl)-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide;

[0190] (5) N-(4-Chlorobenzyl)-4-mercapto-2-(3-hydroxy-1-propynyl)thieno[2,3-b]-pyridine-5-carbothioamide;

[0191] (6)N-(4-Chlorobenzyl)-4-mercapto-2-(3-methoxy-1-propynyl)thieno[2,3-b]-pyridine-5-carbothioamide;

[0192] (7)N-(4-Chlorobenzyl)-4-mercapto-2-(4-hydroxy-1-butynyl)thieno[2,3-b]-pyridine-5-carbothioamide;

[0193] (8)N-(4-Chlorobenzyl)-4-mercapto-2-(3-hydroxypropyl)thieno[2,3-b]pyridine-5-carbothioamide;

[0194] (9)N-(4-Chlorobenzyl)-2-cyano-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide;

[0195] (10) Dimethyl2-[3-(5-{[(4-chlorobenzyl)amino]thiocarbonyl}-4-mercaptothieno-[2,3-b]pyridin-2-yl)-2-propynyl]malonate;

[0196] (11)2-Bromo-N-(4-chlorobenzyl)-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0197] (12)N-(4-Chlorobenzyl)-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide;

[0198] (13)N-(4-Chlorobenzyl)-7-ethyl-2-iodo-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0199] (14)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0200] (15)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0201] (16)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0202] (17)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0203] (18)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0204] (19)2-[5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-2-(3-hydroxy-1-propynyl)-4-thioxothieno[2,3-b]pyridin-7(4H)-yl]aceticacid;

[0205] (20)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0206] (21)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0207] (22)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0208] (23)N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0209] (24)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0210] (25)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0211] (26)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0212] (27)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0213] (28)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0214] (29) 4-{[3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl]oxy}-4-oxobutanoicacid;

[0215] (30) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl2-(4-morpholinyl)acetate;

[0216] (31) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl2-amino-3-methylbutanoate;

[0217] (32) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl3-(4-morpholinylmethyl)benzoate;

[0218] (33)N-(4-chlorobenzyl)-2-(hydroxymethy)-7-methyl-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;

[0219] (34)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;

[0220] (35)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0221] (36)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0222] (37)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0223] (38)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0224] (39)N-(4-chlorobenzyl)-4-mercapto-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carbothioamide;

[0225] (40)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0226] (41)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0227] (42)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0228] (43)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0229] (44)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0230] (45)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylcarbonyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0231] (46)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0232] (437)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0233] (48)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-phenylpropyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0234] (49)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0235] (50)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0236] (51)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0237] (52)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0238] (53)Methyl-5-{[4-chlorobenzyl)amino]thiocarbonyl}-4-mercaptothienol[2,3-b]pyridine-2-carboxylate;

[0239] (54)N-(4-Chlorobenzyl)-4-mercapto-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carbothioamide;and

[0240] (55)N-(4-chlorobenzyl)-4-mercapto-2-(4-morpholinylcarbonyl)thieno[2,3-b]pyridine-5-carbothioamide; or

[0241] a pharmaceutically acceptable salt thereof.

[0242] A specific compound of the invention is,

[0243] (1)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0244] (2)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0245] (3)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0246] (4)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0247] (5)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0248] (6)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0249] (7)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0250] (8)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0251] (9)N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0252] (10)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0253] (11)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0254] (12)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0255] (13)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0256] (14)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0257] (15) 4-{[3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl]oxy}-4-oxobutanoicacid;

[0258] (16) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl2-(4-morpholinyl)acetate;

[0259] (17) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl2-amino-3-methylbutanoate;

[0260] (18) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl3-(4-morpholinylmethyl)benzoate;

[0261] (19)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;

[0262] (20)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0263] (21)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0264] (22)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0265] (23)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0266] (24)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0267] (25)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0268] (26)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0269] (27)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0270] (28)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0271] (29)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0272] (30)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0273] (31)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-phenylpropyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0274] (32)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0275] (33)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0276] (34)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0277] (35)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0278] a pharmaceutically acceptable salt thereof.

[0279] Another specific compound of the invention is,

[0280] (1)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0281] (2)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0282] (3)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0283] (4)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0284] (5)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0285] (6)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0286] (7)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0287] (8)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0288] (9)N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0289] (10)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0290] (11)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0291] (12)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;

[0292] (13)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0293] (14)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0294] (15)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0295] (16)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0296] (17)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0297] (18)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0298] (19)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0299] (20)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0300] (21)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0301] (22)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0302] (23)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0303] (24)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0304] (25)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0305] (26)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0306] (27)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0307] (28)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0308] (29)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0309] (30)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0310] a pharmaceutically acceptable salt thereof.

[0311] A more specific compound of the invention is,

[0312] (1)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0313] (2)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0314] (3)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;

[0315] (4)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0316] (5)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0317] (6)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;

[0318] (7)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0319] (8)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or

[0320] a pharmaceutically acceptable salt thereof.

[0321] Another more specific compound of the invention isN-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamideor a pharmaceutically acceptable salt thereof.

[0322] All cited publications, patents, and patent documents areincorporated by reference herein, as though individually incorporated byreference. The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound of formula I:

or a pharmaceutically acceptable salt thereof wherein, R¹ is (a) Cl, (b)Br, (c) CN, (d) NO₂, or (e) F; R² is (a) H, (b) R⁵, (c) NR⁷R⁸, (d)SO₂R⁹, or (e) OR⁹; R³ is (a) H, (b) halo, (c) aryl, (d) S(O)_(m)R⁶, (e)(C═O)R⁶, (f) (C═O)OR⁹, (g) cyano, (h) het, wherein said het is bound viaa carbon atom, (i) OR¹⁰, (j) Ohet, (k) NR⁷R⁸ (l) SR¹⁰, (m) Shet, (n)NHCOR¹², (O)NHSO₂R¹², or (p) C₁₋₇alkyl which may be partiallyunsaturated and optionally substituted by one or more substituents ofthe group R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸, halo, (C═O)C₁₋₇alkyl, orSO_(m)R⁹; R⁴ is (a) H, (b) halo, (c) C₁₋₄alkyl, or (d) R⁴ together withR³ form a carbocyclic or het, either of which may be optionallysubstituted by NR⁷R⁸, by C₁₋₇alkyl which may be optionally substitutedby OR⁴, or by het, wherein said het is bound via a carbon atom; R⁵ is(a) (CH₂CH₂O)_(i)R¹⁰, (b) het, wherein said het is bound via a carbonatom, (c) aryl, (d) C₁₋₇alkyl which may be partially unsaturated and isoptionally substituted by one or more substituents selected from a groupconsisting of NR⁷R⁸, R¹¹, SO_(m)R⁹, and OC₂₋₄alkyl which may be furthersubstituted by het, OR¹⁰, or NR⁷R⁸, or (e) C₃₋₈cycloalkyl which may bepartially unsaturated and optionally substituted by one or moresubstituents selected from a group consisting of R¹¹, NR⁷R⁸, SO_(m)R⁹,and C₁₋₇alkyl optionally substituted by R¹¹, NR⁷R⁸, or SO_(m)R⁹; R⁶ is(a) C₁₋₇alkyl, (b) NR⁷R⁸, (c) aryl, or (d) het, wherein said het isbound via a carbon atom; R⁷ and R⁸ are independently (a) H, (b) aryl,(c) C₁₋₇alkyl which may be partially unsaturated and is optionallysubstituted by one or more substituents selected from a group consistingof NR¹⁰R¹⁰, R¹¹, SO_(m)R⁹, CONR¹⁰R¹⁰, or halo, or, (d) R⁷ and R⁸together with the nitrogen to which they are attached form a het; R⁹ is(a) aryl, (b) het, (c) C₃₋₈cycloalkyl, or (d) C₁₋₇alkyl which may bepartially unsaturated and is optionally substituted by one or moresubstituents selected from a group consisting of NR¹⁰R¹⁰, R¹¹, SH,CONR¹⁰R¹⁰, or halo; R¹⁰ is (a) H, or (b) C₁₋₇alkyl optionallysubstituted by OH; R¹¹ is (a) OR¹⁰, (b) Ohet, (c) Oaryl, (d) CO₂R¹⁰, (e)het, (f) aryl, or (g) CN; R¹² is (a) H, (b) het, (c) aryl, (d)C₃₋₈cycloalkyl, or (e) C₁₋₇alkyl optionally substituted by NR⁷R⁸ or R¹¹;R¹³ is (a) (P═O)(OR¹⁴)₂, (b) CO(CH₂)_(n)CON(CH₃)—(CH₂)_(n)SO₃ ⁻M⁺, (c)an amino acid, (d) C(═O)aryl, or (e) C(═O)C₁₋₇alkyl optionallysubstituted by NR⁷R⁸, aryl, het, CO₂H, or (O(CH₂)_(n)CO₂R¹⁴); R¹⁴ is (a)H, or (b) C₁₋₇alkyl; each i is independently 2, 3, or 4; each n isindependently 1, 2, 3, 4 or 5; each m is independently 0, 1, or 2; and Mis sodium, potassium, or lithium; wherein any aryl is optionallysubstituted with one or more substituents selected from the groupconsisting of halo, OH, cyano, CO₂R¹⁴, CF₃, C₁₋₆alkoxy, and C₁₋₆ alkylwhich maybe further substituted by one to three SR¹⁴, NR¹⁴R¹⁴, OR¹⁴,het, and CO₂R¹⁴; and wherein any het is optionally substituted with oneor more substituents selected from the group consisting of halo, OH,cyano, phenyl, CO₂R¹⁴, CF₃, C₁₋₆alkoxy, oxo, oxime, and C₁₋₆ alkyl whichmaybe further substituted by one to three SR¹⁴, NR¹⁴R¹⁴, OR¹⁴, andCO₂R¹⁴.
 2. The compound of claim 1 wherein R¹ F, Cl or Br.
 3. Thecompound of claim 1 wherein R¹ is Cl.
 4. The compound of any one ofclaims 1-3 wherein R² is H.
 5. The compound of any one of claims 1-3wherein R² is R⁵, NR⁷R⁸, SO₂R⁹, or OR⁹.
 6. The compound of claim 5wherein R² is R⁵ and R⁵ is C₁₋₇alkyl which may be partially unsaturatedand is optionally substituted by one or more substituents selected froma group consisting of NR⁷R⁸, R¹¹, SO_(m)R⁹, and OC₂₋₄alkyl, which may befurther substituted by het, OR¹⁰, or NR⁷R⁸.
 7. The compound of claim 5wherein R² is R⁵ and R⁵ is C₁₋₇alkyl, which may be partially unsaturatedand is optionally substituted by one or more aryl or het.
 8. Thecompound of claim 7 wherein R⁵ is C₁₋₇alkyl.
 9. The compound of claim 1wherein R² is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,carboxymethyl, (C₁₋₇ alkoxy)carbonylmethyl, 2-hydroxyethyl,2-(2-methoxyethoxy)ethyl, 3-(2-tetrahydropyranyloxy)propyl,2-morpholinoethyl, 2-(diethylamino)ethyl, 2-(dimethylamino)ethyl,2-piperidinoethyl, 3-piperidinopropyl, 2-(1-methylpyrrolidin-2-yl)ethyl,2-(diisopropylamino)ethyl, 2-pyrrolidin-1-ylethyl,3-(dimethylamino)propyl, benzyl, 3-fluorobenzyl, 3-phenylpropyl,2-tetrahydrofuranylmethyl, 2-pyrrolidinoethyl, 3-pyridylmethyl, orvinyl.
 10. The compound of claim 1 wherein R² is methyl, ethyl,isopropyl, 2-hydroxyethyl, 2-(diethylamino)ethyl, or2-(dimethylamino)ethyl.
 11. The compound of claim 1 wherein R³ is H,halo, S(O)_(m)R⁶, (C═O)R⁶, (C═O)OR⁹, cyano, or C₁₋₇alkyl, which may bepartially unsaturated and optionally substituted by one or moresubstituents of the group R¹¹, OR³, SR¹⁰, SR¹³, NR⁷R⁸, halo,(C═O)C₁₋₇alkyl, and SO_(m)R⁹.
 12. The compound of claim 1 wherein R³ isC₁₋₇alkyl which may be partially unsaturated and optionally substitutedby one or more substituents of the group R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸,halo, (C═O)C₁₋₇alkyl, and SO_(m)R⁹.
 13. The compound of claim 1 whereinR³ is C₁₋₇alkyl which may be partially unsaturated and is substituted byone or more substituents of the group R¹¹, OR¹³, SR¹⁰, SR¹³, NR⁷R⁸,halo, (C═O)C₁₋₇alkyl, and SO_(m)R⁹;
 14. The compound of claim 1 whereinR³ is C₁₋₇alkyl which may be partially unsaturated and is substituted byone or more substituents of the group OR¹⁰, het and NR⁷R⁸.
 15. Thecompound of claim 1 wherein R³ is bromo, iodo, 3-hydroxy-1-propynyl,3-methoxy-1-propynyl, 4-hydroxy-1-butynyl, 3-hydroxypropyl, cyano,4,4-di(methoxy-carbonyl)-1-butynyl, 4-hydroxybutyl,3-(3-carboxypropanoyloxy)-1-propynyl, 3-(morpholinoacetoxy)-1-propynyl,3-(2-amino-3-methylbutanoyloxy)-1-propynyl, or thiomorpholinomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl,morpholinocarbonyl, 3-[3-(morpholinomethyl)benzoyloxy]-1-propynyl. 16.The compound of claim 1 wherein R³ is iodo, 3-hydroxy-1-propynyl,4-hydroxy-1-butynyl, 3-hydroxypropyl, morpholimomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl or4-hydroxybutyl.
 17. The compound of claim 1 wherein R³ is3-hydroxy-1-propynyl, morpholimomethyl,N-[2-(4-hydroxyphenyl)-2-hydroxyethyl]-N-(methyl)aminomethyl or3-hydroxypropyl.
 18. The compound of claim 1 which is: (1)N-(4-Chlorobenzyl)-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide; (2)N-(4-Chlorobenzyl)-4-mercapto-2-iodothieno[2,3-b]pyridine-5-carbothioamide;(3)N-(4-Chlorobenzyl)-4-mercapto-2-(4-morpholinylsulfonyl)thieno[2,3-b]-pyridine-5-carbothioamide;(4)2-Bromo-N-(4-chlorobenzyl)-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide;(5)N-(4-Chlorobenzyl)-4-mercapto-2-(3-hydroxy-1-propynyl)thieno[2,3-b]-pyridine-5-carbothioamide;(6) N-(4-Chlorobenzyl)-4-mercapto-2-(3-methoxy1-propynyl)thieno[2,3-b]-pyridine-5-carbothioamide; (7)N-(4-Chlorobenzyl)-4-mercapto-2-(4-hydroxy-1-butynyl)thieno[2,3-b]-pyridine-5-carbothioamide; (8)N-(4-Chlorobenzyl)-4-mercapto-2-(3-hydroxypropyl)thieno[2,3-b]pyridine-5-carbothioamide;(9)N-(4-Chlorobenzyl)-2-cyano-4-mercaptothieno[2,3-b]pyridine-5-carbothioamide;(10) Dimethyl2-[3-(5-{[(4-chlorobenzyl)amino]thiocarbonyl}-4-mercaptothieno-[2,3-b]pyridin-2-yl)-2-propynyl]malonate;(11)2-Bromo-N-(4-chlorobenzyl)-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(12)N-(4-Chlorobenzyl)-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide;(13)N-(4-Chlorobenzyl)-7-ethyl-2-iodo-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(14)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(15)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(16)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(17)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(18)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(19)2-[5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-2-(3-hydroxy-1-propynyl)-4-thioxothieno[2,3-b]pyridin-7(4H)-yl]aceticacid; (20)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(21)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(22)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(23) N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide; (24)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(25)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(26)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(27)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(28)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(29) 4-{[3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl]oxy}-4-oxobutanoicacid; (30) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl2-(4-morpholinyl)acetate; (31) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl2-amino-3-methylbutanoate; (32) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)-2-propynyl3-(4-morpholinylmethyl)benzoate; (33)N-(4-chlorobenzyl)-2-(hydroxymethy)-7-methyl-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;(34)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;(35)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(36)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(37)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(38)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide; (39)N-(4-chlorobenzyl)-4-mercapto-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carbothioamide;(40)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(41)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(42)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(43)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(44)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(45)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylcarbonyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(46)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(437)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(48)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-phenylpropyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(49)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(50)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(51)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(52)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(53)Methyl-5-{[4-chlorobenzyl)amino]thiocarbonyl}-4-mercaptothienol[2,3-b]pyridine-2-carboxylate;(54)N-(4-Chlorobenzyl)-4-mercapto-2-(hydroxymethyl)thieno[2,3-b]pyridine-5-carbothioamide;or (55)N-(4-chlorobenzyl)-4-mercapto-2-(4-morpholinylcarbonyl)thieno[2,3-b]pyridine-5-carbothioamide;or a pharmaceutically acceptable salt thereof.
 19. The compound of claim1 which is: (1)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(2)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(3)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(4)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide; (5)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(6)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(7)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(8)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(9)N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(10)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(11)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(12)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(13)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(14)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(15) 4-{[3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl]oxy}-4-oxobutanoicacid; (16) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl2-(4-morpholinyl)acetate; (17) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl2-amino-3-methylbutanoate; (18) 3-(5-{[(4-Chlorobenzyl)amino]thiocarbonyl}-7-ethyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridin-2-yl)-2-propynyl3-(4-morpholinylmethyl)benzoate; (19)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothienol[2,3-b]pyridine-5-carbothioamide;(20)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(21)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(22)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(23)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(24)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(25)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide; (26)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(27)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(28)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(29)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(30)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(31)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-phenylpropyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(32)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(33)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(34)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or (35)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or a pharmaceutically acceptable salt thereof.
 20. The compound of claim1 which is: (1)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(2)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxy-1-butynyl)-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(3)N-(4-Chlorobenzyl)-7-ethyl-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(4)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(5)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxy-1-propynyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(6)N-(4-Chlorobenzyl)-7-ethyl-2-(4-hydroxybutyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(7)N-(4-Chlorobenzyl)-7-(2-hydroxyethyl)-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(8)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(9)N-(4-Chlorobenzyl)-2-iodo-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(10)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(11)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(12)N-(4-Chlorobenzyl)-2-iodo-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]-pyridine-5-carbothioamide;(13)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-isopropyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(14)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-isopropyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(15)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(16)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(17)N-(4-chlorobenzyl)-7-methyl-4-thioxo-2-(4-thiomorpholinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(18)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)-(methyl)amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(19)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(20)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(21)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(22)N-(4-Chlorobenzyl)-7-isopropyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(23)N-(4-Fluorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(24)N-(4-bromobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(25)7-Benzyl-N-(4-chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(26)N-(4-Chlorobenzyl)-7-(3-fluorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(27)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(tetrahydro-2-furanylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(28)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-[2-(1-pyrrolidinyl)ethyl]-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(29)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(3-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or (30)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-(4-pyridinylmethyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or a pharmaceutically acceptable salt thereof.
 21. The compound of claim1 which is: (1)N-(4-Chlorobenzyl)-7-[2-(diethylamino)ethyl]-2-(3-hydroxypropyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(2)N-(4-Chlorobenzyl)-2-(3-hydroxy-1-propynyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(3)N-(4-Chlorobenzyl)-2-(3-hydroxypropyl)-7-methyl-4-thioxo-4,7-dihydro-thieno[2,3-b]pyridine-5-carbothioamide;(4)N-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(5)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-(4-hydroxyphenyl)ethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(6)N-(4-chlorobenzyl)-2-(((2-hydroxy-2-phenylethyl)(methyl)-amino)methyl)-7-methyl-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;(7)N-(4-Chlorobenzyl)-7-ethyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or (8)N-(4-Chlorobenzyl)-2-(4-morpholinylmethyl)-4-thioxo-7-propyl-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamide;or a pharmaceutically acceptable salt thereof.
 22. The compoundN-(4-chlorobenzyl)-7-methyl-2-(4-morpholinylmethyl)-4-thioxo-4,7-dihydrothieno[2,3-b]pyridine-5-carbothioamideor a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a compound of any one of claims 1 to 22 and apharmaceutically acceptable excipient.
 24. A method for treating aherpesviral infection, comprising administering to a mammal in need ofsuch treatment, an effective amount of a compound of claim
 1. 25. Themethod of claim 24 wherein the herpesviral infection is herpes simplexvirus type 1, 2, 6, 7, or 8, varicella zoster virus, humancytomegalovirus, or Epstein-Barr virus.
 26. The method of claim 24wherein the herpesviral infection is herpes simplex virus type 1, herpessimplex virus type 2, varicella zoster virus, human cytomegalovirus,Epstein-Barr virus, human herpes viruses 7 or human herpes viruses 8.27. The method of claim 24 wherein the herpesviral infection is humancytomegalovirus.
 28. A method for treating atherosclerosis or restenosisin a mammal comprising, administering to a mammal in need of suchtreatment, an effective amount of a compound of claim
 1. 29. A methodfor inhibiting a viral DNA polymerase comprising contacting thepolymerase with an effective inhibitory amount of a compound of claim 1.30. A method for preparing a thioxo-carbothioamide compound of formulaI:

wherein R¹-R⁴ have the values in claim 1, comprising reacting acorresponding compound of formula II:

with a suitable thionating reagent to provide the compound of formula I.